The Akt signaling pathway is an important regulator of multiple biological processes, such as apoptosis, cell proliferation, and metabolism. This pathway is frequently upregulated in human cancers through a number of different mechanisms, thereby promoting the survival of cancer cells and contributing to the clinical challenges of treating cancer patients. Complete activation of Akt requires phosphorylation at two amino acid residues: threonine-308 (T308), which is phosphorylated by phosphoinositide-dependent kinase 1 (PDK1), and serine-473 (S473), which is known as the PDK2 site and has been reported to be phosphorylated by a number of different kinases. One of these, integrin-linked kinase (ILK), has been identified as a promising anti-cancer target as its expression and activity are increased in various types of cancer, and its inhibition can suppress cancer cell survival by inducing apoptosis and cell-cycle arrest (Hannigan et al., Nature Reviews Cancer 5, 51 (2005)). The development of novel, potent, and safe inhibitors of ILK could provide new targeted therapeutics for the treatment of cancer.
The inventors have previously prepared a number of celecoxib derivatives for use as PDK-1/Akt signaling inhibitors, or for other applications. For example, U.S. Pat. Nos. 7,026,346 and 7,576,116 and Patent Publication No. 2008/0269309 describe a number of compounds useful as PDK-1/Akt signaling inhibitors and anticancer agents. U.S. patent application Ser. No. 12/428,035 by inventors describes a number of celecoxib derivatives that are useful for treating infection by Francisella bacteria.
Small-molecule inhibitors of ILK have also been reported. Among these, QLT0267 seems to have garnered recent interest as it has shown efficacy in preclinical studies (Kalra et al., Breast Cancer Res 11, R25 (2009); Eke et al., PLoS ONE 4: e6434 (2009); Edwards et al., Mol Cancer Ther 7, 59 (2008)). In breast cancer cells, the reported IC50 values of QLT0267 for inhibition of cell viability ranged from 9.8-70.9 μM after 72 h treatment in vitro, and in vivo dosing via the oral or intraperitoneal routes required/used 100 or 200 mg/kg to suppress tumor growth in mice. However, there remains a need for additional ILK inhibitors, particularly those exhibiting high levels of activity.